**5. Therapeutic approach**

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

aldosterone system (RAAS) are described [33].

**4. Hyperglycemia and CVD relationship**

3.67; p < 0.05) [38],

disease and stroke [40, 41],

coronary heart disease, valvulopathies, or other FRCV, in patients with diabetes, especially with long-term diabetes and poor control." Fibrosis, stiffness, and cardiac hypertrophy are basic changes, which are initially associated with diastolic dysfunction, LV hypertrophy and reduced compliance with preserving the ejection fraction, later evolving into systolic dysfunction clinically manifest HF [16, 33]. As risk factors of diabetic cardiomyopathy, hyperglycemia, dyslipidemia, altered energy metabolism, dysregulated insulin signaling, inflammation, endoplasmic reticular stress, mitochondrial dysfunction, oxidative stress and accumulation of advanced glycation end-products (AGEs) and activation of the renin-angiotensin-

Compared with individuals without diabetes, patients with T2DM are disproportionately affected by CVD morbidity and mortality. Most of this excess risk is associated with an increased prevalence of risk factors such as hypertension, dyslipidemia, and obesity in these patients. However, hyperglycemia, as a distinct characteristic of DM, appears to be an independent risk factor for all-cause and

CVD mortality independent of other modifiable CVD risk factors:

increased risk of important adverse CV events [35–37],

• Increased HbA1c is associated with coronary heart disease [34],

• Long-term intraindividual variability of HbA1c or basal blood glucose is associated with micro-and macro-vascular complications and with an

• 24-hour glycemic variability, greater than 35.9 mg/dl, is independently

associated with an increased risk of left ventricular diastolic dysfunction, even in asymptomatic patients and with a preserved ejection fraction (odds ratio:

• Basal glycemia >126 mg/dl was associated with a risk of fatal/non-fatal coronary heart disease, fatal/non-fatal stroke of 39% in women and 48% in men [39],

• Each 1-point increase in HbA1c is associated with an 8% increase in the risk of

• The onset of diabetes in young people and the long duration of diabetes, are associated with an increased risk of mortality, mainly CV, due to ischemic

• The risk of coronary artery disease increases in diabetic patients by 11% for each 1% increment in HbA1c greater than 6.5%. In adults with diabetes, but without baseline CVD, an HbA1c of 9% is correlated with an increased risk of myocardial infarction or acute coronary syndrome (odds ratio [OR] = 1.18),

• Severe hypoglycemia is linked with an increased risk of recurrence (especially in T1DM) and an increased risk of CV events, including death. In the Veteran Affairs Diabetes Trial, severe hypoglycemia was associated in the following 3 months with CV events (HR = 1.9; p = 0.03), CV mortality (HR = 3.7;

HF and a 36% increased risk for HF hospitalization [16, 39],

stroke (OR = 1.29) and heart failure (OR = 1.37) [42],

p = 0.01) and mortality of any cause (HR = 2.4; p = 0.02) [43].

**282**

The major objectives of clinical management in T2DM are preventing or delaying chronic complications, increasing life expectancy, and quality. The basic principle of clinical management is the "patient-centred" approach, respectively, the intervention's individualisation [19]. The significant reduction of cardiovascular morbidity/mortality implies a multifactorial approach, addressed simultaneously to all CV risk factors. The 7.8-year STENO-2 study, which included patients with T2DM with increased CV risk (microalbuminuria), showed that the multifactorial approach significantly reduced mortality from any cause (20% reduction in absolute risk), 13% in CV mortality and 29% in the absolute risk of CV events [44, 45]. The 21-year assessment showed that life expectancy was extended by eight years in the intensive care group, and the relative risk of HF was reduced by 76% [45]. Analysis of data from an extensive registry has shown that in people with T2DM, simultaneous control of major CV risk factors (blood glucose, blood pressure, cholesterol and lifestyle, no smoking), can reduce over 60% of cardiovascular and coronary atherosclerotic events [46]. Patients with diabetes who have five risk-factor variables within the target ranges (HbA1c, LDL-cholesterol, blood pressure, no albuminuria and no smoking) seem to have lower or no excess risk of overall death or myocardial infarction and/or stroke, as similar to the general population, as shown in a study that included 271,174 patients with T2DM registered in the Swedish National Diabetes Register [47].
